ESC Congress 2026 featured several arrhythmia-related clinical trials. SINGLE-AF investigated anticoagulation in patients with atrial fibrillation (AFib) and intermediate stroke risk, PVI-SHAM-AF compared whether catheter ablation improves AFib-related quality of life more than a sham procedure, ASPIRED tested 14-day ECG monitoring in patients with unexplained syncope, and DANISH-CRT examined whether targeting the left ventricular (LV) lead at site of latest electrical activation improves outcomes in patients with heart failure (HF) and prolonged QRS.

SINGLE-AF: DOACs Benefit AFib Patients With Intermediate Stroke Risk

SINGLE-AF is the first randomized trial to compare oral anticoagulation with no anticoagulation in patients with AFib with intermediate stroke risk (CHA₂DS₂-VASc score of 1 in men or 2 in women),¹ a population that current guidelines address with a Class 2a recommendation.² This multicenter, open-label trial randomly assigned 1,803 patients in South Korea to direct oral anticoagulant (DOAC) therapy or no anticoagulation.

At 24 months, the primary endpoint (a composite of stroke, systemic embolism, major bleeding, or cardiovascular death) occurred in four patients on DOAC therapy vs. 13 patients in the no anticoagulation group (hazard ratio [HR], 0.31; 95% CI, 0.10-0.94). This difference was predominantly driven by a reduction in stroke: three in the DOAC group vs. 10 in the no anticoagulation group (HR, 0.30; 95% CI, 0.08-1.08). All 10 strokes in the no anticoagulation group were ischemic, with two disabling; two of the three DOAC group strokes were hemorrhagic, with one disabling.

Major bleeding was similar between groups, and intracranial hemorrhage occurred in two DOAC patients vs. one. The cohort was young and at low baseline bleeding risk, and about one third of the no anticoagulation group received antiplatelet therapy. The benefit was concentrated in preventing nondisabling ischemic strokes, and the small event count limits precision.

AFib burden is increasingly recognized as a stroke risk factor not captured by clinical risk scores. Most patients had paroxysmal AFib, and approximately one third had already undergone catheter ablation. ALONE-AF and OCEAN trials addressed a related question after ablation: Despite an older, higher-risk population than SINGLE-AF, ALONE-AF investigators found a lower stroke rate among patients off anticoagulation once free of arrhythmia recurrence, suggesting AFib burden may be an emerging, modifiable target for stroke risk stratification.

Bottom Line

In patients with AFib at intermediate stroke risk, DOAC therapy reduced the composite primary endpoint compared with no anticoagulation, driven mainly by fewer nondisabling ischemic strokes. SINGLE-AF adds meaningful evidence to support a shared decision-making conversation about anticoagulation in this population. Future studies that account for AFib burden and include a broader population, particularly patients with higher AFib burden, may help strengthen this recommendation.

PVI-SHAM-AF: Ablation Not Superior to Sham Procedure for AFib Quality of Life

Catheter ablation is guideline recommended for symptom relief in AFib.² Until recently, however, the supporting quality-of-life data came only from open-label trials, leaving open how much of the perceived benefit reflects the objective success of the procedure vs. the patient's actual experience. PVI-SHAM-AF, a double-blind, sham-controlled trial at nine centers in Germany and Poland, randomized 262 patients with symptomatic paroxysmal or persistent AFib 2:1 to catheter ablation (n=173) or a sham procedure (n=89) incorporating sedation, venous access, and cardioversion when needed.³

The primary endpoint, change in Atrial Fibrillation Effect on the Quality-of-Life Questionnaire (AFEQT) summary score at 6 months, was neutral by the prespecified Hodges-Lehmann analysis (2.6 points, 95% CI, −2.7 to 8.0; p=0.36), although a mixed-model sensitivity analysis showed a significant 5.4-point difference (95% CI, 1.0 to 9.8). Rhythm control clearly favored ablation, with AFib on 7-day Holter in 21% vs. 41% of patients, and a clinical plus Holter composite recurrence of 27% vs. 48%. In the sham arm, 12% underwent cardioversion during follow-up, and 52% remained AFib free at 6 months.

PVI-SHAM-AF did not meet its primary endpoint, but that should not be read as "ablation equals placebo." Rhythm control was superior in the ablation arm, with approximately one half the AFib burden and recurrence of sham. The quality-of-life result was murkier because one statistical method showed no real difference between groups, whereas another showed a modest one favoring ablation. The real message here is about the comparator, not the intervention.

Bottom Line

This trial estimates the benefit of ablation over an active, temporary rhythm-control pathway, not over doing nothing. For patient counseling, the practical message stays the same. Ablation reliably reduces AFib burden and recurrence, although other rhythm-control strategies can achieve some of that too. Longer follow-up at 12 months should help clarify things further.

ASPIRED: 14-Day ECG Monitoring Does Not Significantly Lower Syncope Episodes vs. Standard Care

ASPIRED was an open-label, randomized, multicenter trial from the United Kingdom evaluating 14-day continuous ambulatory cardiac monitoring in patients presenting to the emergency department with syncope that remained unexplained after initial assessment.⁴ Investigators randomized 2,234 patients, 1,123 to a 14-day ambulatory ECG patch initiated at the index visit and 1,111 to standard care.

The primary endpoint, the mean number of patient-reported syncopal episodes at one year, did not differ between groups (1.37 ± 5.10 in the intervention group vs. 1.58 ± 8.56 in the standard-care group; incidence rate ratio, 0.89; 95% CI, 0.68-1.18; p=0.42). Syncope recurrence was also similar (27.9% vs. 28.6%). Monitoring increased arrhythmia detection: A clinically significant cardiac arrhythmia was identified in 22.0% of the intervention group vs. 9.0% of the standard-care group (odds ratio, 2.95; 95% CI, 2.28-3.81). This was driven mainly by nonsustained ventricular tachycardia, defined as ≥4 beats at 120 bpm, unlikely by itself to explain syncope, which accounted for 109 of the detected arrhythmias. Pacemaker implantation was modestly higher (6.8% intervention vs. 4.6% standard care).

The primary endpoint relied on self-reported episodes captured through four weekly questionnaires, and the standard deviations exceeding the means indicated that a small number of high frequency reporters drove the result. When a sensitivity analysis excluded 11 outlying participants, the effect reversed, from a rate ratio of 0.89 favoring monitoring to 1.07 favoring standard care (95% CI, 0.83-1.38).

Bottom Line

Syncope is a subjective, patient-reported outcome, which makes it a difficult target to move even when an intervention changes what is detected. ASPIRED reinforces that diagnostic yield of an intervention may not translate into patient benefit: A blanket 14-day monitoring strategy detected more rhythm abnormalities without altering syncope burden. These findings underscore the importance of identifying which patients are most likely to benefit from monitoring rather than applying it uniformly.

DANISH-CRT: Targeted Lead Placement No Better Than Standard Placement in CRT

For over a decade, observational data have suggested that CRT nonresponse is partly a function of where the LV lead is implanted in relation to the site of latest LV electrical activation, yet there was no adequately powered randomized controlled trial exploring this despite guideline recommendations for CRT in appropriately selected patients.

The DANISH-CRT multicenter randomized trial included 1,001 patients with HF, LVEF ≤35%, and wide QRS (left bundle branch block ≥130 msec, other bundle branch block >150 msec, or right ventricular-paced) to LV lead placement guided by coronary sinus electrical mapping (targeting latest activation) vs. conventional posterolateral, nonapical placement, with a primary composite endpoint of time to death or first unplanned HF hospitalization.⁵

The mapping strategy successfully identified and captured the latest-activated branch in 83% of intervention patients, but the delay it achieved over standard practice was modest, a mean of only 9 msec. Anatomically, LV lead locations on CT were nearly identical between groups, clustered posterolaterally, and there was no difference in paced QRS duration.

During a median follow-up of 45.8 months, the primary composite endpoint occurred in 28% of the intervention group vs. 26% of controls (HR, 1.10; 95% CI, 0.86-1.39; p=0.45), with no signal favoring mapping across any prespecified subgroup. Notably, unplanned HF hospitalization alone was significantly higher with mapping (15% vs. 11%; HR, 1.47; 95% CI, 1.03-2.08; p=0.03), and lead-related complications trended higher (7% vs. 5%), alongside longer procedure times (100 vs. 81 min) and greater radiation exposure (19 vs. 14 Gycm²).

Bottom Line

CRT delivered through a coronary sinus lead is inherently limited to anatomically accessible branches, even when the true site of latest LV activation lies beyond that reach in a heterogeneous HF population with differing etiologies. As the trial authors conclude, a posterolateral, nonapical branch remains the right default for most patients. Other approaches such as WiSE-CRT (leadless LV endocardial pacing) and conduction system pacing may be better positioned to exploit activation-guided targeting going forward.

References

1. Kim D, Lee YS, Shim J, et al. Anticoagulation for atrial fibrillation with intermediate stroke risk. N Engl J Med. 2026;395(12):1155-1165. doi:10.1056/NEJMoa2607978
2. Writing Committee Members, Joglar JA, Chung MK, et al. 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83(1):109-279. doi:10.1016/j.jacc.2023.08.017
3. Wachter R, Haag P, Uhe T, et al. Catheter ablation for symptomatic atrial fibrillation (PVI-SHAM-AF): a randomised, double-blind, sham-controlled, multicentre trial. Lancet. 2026;408(10559):999-1009. doi:10.1016/S0140-6736(26)01558-8
4. Reed MJ, Goodacre S, Weir CJ, et al. Immediate ambulatory electrocardiographic monitoring in syncope. N Engl J Med. Published online August 31, 2026. doi:10.1056/NEJMoa2605812
5. Nielsen JC, Svendsen JH, Johansen JB, et al. Targeted left ventricular lead placement in biventricular pacing for heart failure: a national, multicentre, double-blind, randomised controlled trial in Denmark. Lancet. Published online August 31, 2026. doi:10.1016/S0140-6736(26)01597-7